G. Miolo et al., New benzoquinolizin-5-one derivatives as furocoumarin analogs: DNA-interactions and molecular modeling studies, FARMACO, 54(8), 1999, pp. 551-561
Three derivatives of 1H, 5H and 3H,SH-benzo[ij]quinolizin-5-one (BQZ(1)), p
reviously prepared by chemical synthesis with the aim of obtaining furocoum
arin analogs, have been studied. These are able to intercalate inside DNA a
nd by subsequent irradiation with UVA light, to photoreact with DNA. Compou
nd I (10-methoxy-7-methyl-1H, 5H-benzo[ij]quinolizin-5-one) has a potential
ly photoreactive 2, 3 double bond because of its conjugation with the pyrid
ine ring of quinolinone, while compounds II (10-acetoxy-7-methyl-3H, 5H-ben
zo[ij]quinolizin-5-one) and III (10-methoxy-7-methyl-3H,SH-benzo[ij]quinoli
zin-5-one) have a potentially photoreactive 1,2 double bond conjugated with
the benzene ring of quinolinone. Compounds I and III, having a tricyclic p
lanar structure, intercalate inside the DNA, while compound II cannot inter
calate efficiently because of the steric hindrance of the acetoxy group in
10, lying outside the plane of the molecule and rotated by an angle of 77.6
degrees with respect to the tricyclic plane. The photoreaction of BQZ with
DNA structure, as already known for psoralen and angelicin derivatives, co
nsists of a [2 + 2] photocycloaddition reaction with the pyrimidine bases.
The main photoadduct between the 2,3 double bond of I and the 5, 6 double b
ond of thymine has been isolated and characterized by NMR, showing a cis-an
ti structure. Theoretical calculations, using AMI Hamiltonian, have been ca
rried out to describe the photocycloaddition reaction mechanism better. Fro
m a theoretical point of view, in the case of BQZ both the 1,2 or 2,3 doubl
e bonds and the 6, 7 double bond may be involved in the [2 + 2] photocycloa
ddition. Spin densities and molecular orbital symmetries of compound I, in
its triplet state, suggest that the 2,3 double bond interacts favorably wit
h the 5,6 double bond of thymine moiety. On the contrary, the acetoxy subst
ituent in position 10 of II seems to play a negative role in the DNA interc
alation process. (C) 1999 Elsevier Science S.A. All rights reserved.